PROJECT SUMMARY/ABSTRACT Clinical trials for neurodegenerative diseases are hampered by the lack of quantitative and objective biomarkers that reflect treatment effects in the brain. Magnetic resonance spectroscopy (MRS) has potential to directly assess disease-modifying effects of therapeutic interventions in the brain. However, MRS has not made the transition to the clinical setting, largely due to lack of standardization of data acquisition and analysis methods and compromised data quality obtained with standard clinical packages, which result in poor reproducibility of neurochemical concentrations. The primary objective of this project is to facilitate translation of advanced MRS technology to the clinical setting in a strategic alliance between MR physicists, software engineers and physician scientists. This Partnership for MRS Biomarker Development is comprised of 3 phases and incorporates a gradual shift from MRI/MRS to clinical expertise at the sites involved: Phase I has established an MR- technologist ready advanced MRS protocol on two widely-used clinical 3T platforms (Siemens and Philips). Phase II is assessing the performance of the protocol under ideal conditions (efficacy), namely at sites where MRI/S and clinical trial expertise overlap. We focus on hereditary spinocerebellar ataxias (SCA) because the patient cohorts are well-characterized and they present the greatest need for multi-center investigations to sufficiently sample the patient population in trials. Finally, Phase III will assess the performance of the protocol under ordinary conditions (effectiveness), i.e. in a clinical setting with rotating MR technologists. This phase will focus on Alzheimer disease (AD), the most common cause of age associated cognitive decline and dementia, and take advantage of large ongoing neuroimaging investigations. We now have an unanticipated opportunity to implement and test the advanced MRS protocol on all 3 major MRI scanner platforms (Siemens, Philips and GE) by utilizing the GE platform instead of Philips at one of the Phase III sites, University of Michigan. The MRS pulse sequence has already been implemented on the GE platform in collaboration with the Global Spectroscopy Leader of GE Healthcare. This administrative supplement is requested to support the additional testing that will be required at U Michigan to implement the full protocol, including communication of the MRS sequence with additional technology we have developed in Phase I, to automate volume-of-interest selection.